Dynamic Interaction between STLV-1 Proviral Load and T-Cell Response during Chronic Infection and after Immunosuppression in Non-Human Primates

We used mandrills (Mandrillus sphinx) naturally infected with simian T-cell leukemia virus type 1 (STLV-1) as a model for evaluating the influence of natural STLV-1 infection on the dynamics and evolution of the immune system during chronic infection. Furthermore, in order to evaluate the role of the immune system in controlling the infection during latency, we induced immunosuppression in the infected monkeys. We first showed that the STLV-1 proviral load was higher in males than in females and increased significantly with the duration of infection: mandrills infected for 10–6 years had a significantly higher proviral load than those infected for 2–4 years. Curiously, this observation was associated with a clear reduction in CD4+ T-cell number with age. We also found that the percentage of CD4+ T cells co-expressing the activation marker HLA-DR and the mean percentage of CD25+ in CD4+ and CD8+ T cells were significantly higher in infected than in uninfected animals. Furthermore, the STLV-1 proviral load correlated positively with T-cell activation but not with the frequency of T cells secreting interferon γ in response to Tax peptides. Lastly, we showed that, during immunosuppression in infected monkeys, the percentages of CD8+ T cells expressing HLA-DR+ and of CD4+ T cells expressing the proliferation marker Ki67 decreased significantly, although the percentage of CD8+ T cells expressing HLA-DR+ and Ki67 increased significantly by the end of treatment. Interestingly, the proviral load increased significantly after immunosuppression in the monkey with the highest load. Our study demonstrates that mandrills naturally infected with STLV-1 could be a suitable model for studying the relations between host and virus. Further studies are needed to determine whether the different compartments of the immune response during infection induce the long latency by controlling viral replication over time. Such studies would provide important information for the development of immune-based therapeutic strategies

Numbers of samples collected from wild-born chimpanzees by geographic origin, sex and SIV status.

*<p>Juvenile that died at 3 months.</p

Hematologic and immunologic parameters of chimpanzee Gab4 and of 16 uninfected chimpanzees.

<p>CM, central memory; EM, effector memory.</p>*<p>p<0.05 determined with Mann-Witney <i>U</i> test.</p

The Amplification strategy and the genome structure of the new SIVcpz identified strain.

<p>(A) Amplification strategy (primers listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044298#pone.0044298.s001" target="_blank">Table S1</a>); (B) genome structure of SIVcpz-Gab4, depending on frame. Each gene is represented by a rectangular box with the name inside and its position within the genome. Arrows point to gene spread over two locations.</p

Western blot profiles of SIV-positive chimpanzees from Gabon.

<p>Plasma samples from chimpanzees Gab3 and Gab4 were tested for the presence of HIV-1 cross-reactive antibodies by western immunoblotting. Strips A and B are negative and positive controls, respectively. Progressive loss of HIV-cross-reactive antibodies in chimpanzee Gab3 is represented on strips C (at arrival, age 1 month), D (2 months), and E (death at 3 months). Strip F illustrates the HIV-1 cross-reactivity in plasma from chimpanzee Gab4.</p

New Strain of Simian Immunodeficiency Virus Identified in Wild-Born Chimpanzees from Central Africa

<div><p>Studies of primate lentiviruses continue to provide information about the evolution of simian immunodeficiency viruses (SIVs) and the origin and emergence of HIV since chimpanzees in west–central Africa (<em>Pan troglodytes troglodytes</em>) were recognized as the reservoir of SIVcpz<em>Ptt</em> viruses, which have been related phylogenetically to HIV-1. Using in-house peptide ELISAs to study SIV prevalence, we tested 104 wild-born captive chimpanzees from Gabon and Congo. We identified two new cases of SIVcpz infection in Gabon and characterized a new SIVcpz strain, SIVcpz<em>Ptt</em>-Gab4. The complete sequence (9093 bp) was obtained by a PCR-based ‘genome walking’ approach to generate 17 overlapping fragments. Phylogenetic analyses of separated genes (<em>gag, pol-vif</em> and <em>env-nef</em>) showed that SIVcpz<em>Ptt</em>-Gab4 is closely related to SIVcpz<em>Ptt</em>-Gab1 and SIVcpz<em>Ptt</em>-Gab2. No significant variation in viral load was observed during 3 years of follow-up, but a significantly lower CD4+ T cells count was found in infected than in uninfected chimpanzees (<em>p</em><0.05). No clinical symptoms of SIV infection were observed in the SIV-positive chimpanzees. Further field studies with non-invasive methods are needed to determine the prevalence, geographic distribution, species association, and natural history of SIVcpz strains in the chimpanzee habitat in Gabon.</p> </div

Predicted protein sequence of the <i>env</i> gene (gp120 and gp41) of SIVcpz-Gab4 in comparison with SIVcpz-Gab1 and SIVcpz-Gab2.

<p>Conserved cysteines are marked with asterisks, variable regions V1–V5 are indicated, and the CD4 binding site and immunodominant transmembrane domain are highlighted in grey.</p

Protein sequence identities among SIVcpz/HIV-1 viruses.

<p>Protein sequence identities among SIVcpz/HIV-1 viruses.</p

Diversity plot of SIVcpz-Gab4 with SIVcpz-Gab1 and SIVcpz-Gab2 sequences.

<p>Regions with uncertain aligment or sites with a gap in any sequence were excluded (8261 nucleotides after de-gapping). The nucleotide sequence difference is plotted for windows of 450 nucleotides and a 20-nucleotide step increment.</p

Prevalence and Molecular Diversity of Hepatitis B Virus and Hepatitis Delta Virus in Urban and Rural Populations in Northern Gabon in Central Africa▿

The prevalence of hepatitis B virus (HBV) surface antigen was significantly higher in urban (12.9%) than in rural (7.6%) populations (P = 0.003), but no difference was found in the prevalence of hepatitis delta virus (HDV), which was high in both populations. Phylogenetic analysis showed the circulation of HBV-A3 and -E genotypes and the presence of HDV-1, HDV-7, and HDV-8 clades